TRPA1 (ANKTM1, p120) is a non-selective cation channel that belongs to the Transient Receptor Potential (TRP) superfamily. TRPA1 was first identified as a transformation sensitive mRNA in cultured human lung fibroblasts (Jaquemar et al., J Biol. Chem., 1999, 274, 7325-7333). Subsequent studies indicated that TRPA1 was also highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia, and in hair cells of the inner ear (Story et al., Cell, 2003, 112, 819-829; Corey et al., Nature, 2004, 432, 723-730; Nagata et al., J. Neurosci., 2005, 25, 4052-4061; Diogenes et al., J Dent Res., 2007, 86, 550-555). In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it co-localizes with markers of peptidergic nociceptors such as TRPV1, CGRP and substance P (Story et al., supra; Bautista et al., PNAS, 2005, 102, 12248-12252; Nagata et al., J Neurosci., 2005, 25, 4052-4061; Diogenes et al., J Dent Res., 2007, 86, 550-555).
The finding that TRPA1 is expressed in small diameter nociceptors has led to the suggestion that this channel may be involved in pain sensation. Indeed a number of additional observations support this suggestion. For example, TRPA1 expression can be increased by inflammatory mediators such as NGF (Diogenes et al., J Dent Res., 2007, 86, 550-555) and following nerve injury or inflammation (Obata et al., J Clin Invest. 2005, 115, 2393-2401; Frederick et al., Biochem Biophys Res Commun., 2007, 358, 1058-1064). Bradykinin, a potent algogenic peptide released at sites of injury and inflammation, can activate TRPA1 via G-protein coupled BK2 receptors (Bandell et al., Neuron, 2004, 41, 849-857). In addition, TRPA1 can be activated by a range of pungent or irritant compounds that can elicit pain in animals and humans, such as mustard oil (AITC), cinnamaldehyde, acreolin, allicin, and formalin (Bandell et al., supra; Namer et al., Neuroreport, 2005, 16, 955-959; Bautista et al., Cell, 2006, 124, 1269-1282; Fujita et al., Br J. Pharmacol., 2007, 151, 153-160; McNamara et al., PNAS, 2007, 104, 13525-13530). TRPA1 may also be activated by noxious cold (Bandell et al., Neuron, 2004, 41, 849-857; Jordt et al., Nature, 2004, 427, 260-265; Nagata et al., J Neurosci., 2005, 25, 4052-4061). In behavioral studies, intra-thecal TRPA1 anti-sense oligodeoxynucleotide suppressed inflammation and nerve injury-induced cold allodynia (Obata et al., J Clin Invest., 2005, 115, 2393-2401) and mustard oil induced pain behaviors and bradykinin-induced acute pain and hyperalgesia are abolished in TRPA1−/− mice (Bautista et al., supra; Kwan et al., Neuron, 2006, 50, 277-289).
In a formalin-induced pain model, TRPA1 has been shown to be the principal site of formalin's pain-producing action in vivo, and activation of TRPA1 underlies the physiological and behavioral responses associated with this model of pain. Formalin induced activation of the TRPA1 channel has been shown to be attenuated by TRPA1 antagonists (McNamara et al., PNAS, 2007, 104, 13525-13530).
Treatment with cigarette smoke extracts (CSE) increased Ca2+ influx in TRPA1-transfected cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data suggest a role for TRPA1 in the pathogenesis of CSE-induced diseases such as Chronic obstructive pulmonary disease, or COPD (André et al., J Clin Invest., 2008, 118, 2574-2582).
In addition, TRPA1 activation by various oxidants and products of lipid peroxidation, such as 4-hydroxynonenal and 4-oxononenal, is suggested to be a key mechanism that links oxidative stress to nocifensive responses in the airway (Taylor-Clark et al., J. Physiol., 2008, 586, 3447-3459; Trevisani et al., PNAS, 2007, 104, 13519-13524; Andersson et al., J. Neurosci., 2008, 28, 2485-2494). TRPA1 is discussed to represent a new target for the development of drugs that suppress neuronal hypersensitivity in individuals with airway disease such as asthma, chronic cough and reactive airway dysfunction syndrome (Bessac and Jordt, Physiology, 2008, 23, 360-370).
A recent study showed that a variety of the known electrophilic tear gasses used in the past and present as riot control or incapacitating agents, are potent activators of the human TRPA1 channel (Brone et al., Toxicol & Appl Pharmacol., 2008, 231, 150-156; Bessac et al., FASEB J., 2008, Nov. 26 e-pub). Thus antagonism of the TRPA1 channel could have use for military and police applications as defense against such agents.
TRPA1 is also expressed in bladder and urethra urothelium, epithelium and nerve fibers of the urothelium, sub-urothelial space, muscle layers and around blood vessels (Du et al., Urology, 2008, 72, 450-455; Andrade et al., Biochem Pharmacol., 2006, 72, 104-114; Gratzke et al., Eur Urology, 2008, Apr. 30 e-pub; Streng et al., Eur Urology, 2008, 53, 391-400). TRPA1 expression is increased in bladder mucosa from patients with bladder outlet obstruction (Du et al., Urology, 2008, 72, 450-455). Activation of TRPA1 causes increased micturition frequency and reduced voiding volume (Streng et al., supra). Activation of TRPA1 in the bladder by reactive metabolites of cyclophosphamide (e.g., acrolein) may be responsible for cystitis that sometimes accompanies the use of chemotherapeutic agents (Bautista et al., supra). TRPA1 is also expressed in colonic afferents, is upregulated following induction of experimental colitis, and TRPA1 antisense oligonucleotides suppressed colitis-induced hyperalgesia to colonic distension (Yang et al., Neurosci Lett., 2008, 440, 237-241). These data suggest a role for TRPA1 in the pathogenesis of visceral pain and dysfunction, such as bladder instability, urinary incontinence, cystitis and colitis.
TRPA1 may also be activated by general anesthetics such as isoflurane (Matta et al., PNAS, 2008, 105, 8784-8789), suggesting a possible role for TRPA1 antagonists in post-surgical pain. In addition, TRPA1 can be activated by a variety of skin sensitizers, natural products (Escalera et al., JBC, 2008, 283, 24136-24144) and ethanol metabolites (Bang et al., Eur J. Neurosci., 2007, 26, 2516-2523), suggesting roles for TRPA1 antagonists in the treatment of contact dermatitis, and the symptoms of “hangover” (i.e., headache, nasal congestion, facial flushing).
Certain diamine-substituted pyridines are described in the following publications: Intl. Pat. Appl. Publ. WO 1991/09849 (Upjohn, Jul. 11, 1991); Intl. Pat. Appl. Publ. WO 2006/063718 (Hoffmann La Roche, Jun. 22, 2006); U.S. Pat. No. 4,788,196 (Pfizer, Nov. 29, 1988); and U.S. Pat. No. 4,806,536 (Pfizer, Feb. 21, 1989). Certain β-Alanine derivatives are disclosed in U.S. Pat. No. 6,645,939 (Merck & Co., Inc.).
Still further, certain compounds were obtained from a third party. The compounds are identified herein as Examples 189 to 225 and 286 to 316.
However, there remains a need for potent histamine TRPA1 receptor modulators with desirable pharmaceutical properties. Certain heterocyclic amide derivatives have been found in the context of this invention to have TRPA1 receptor-modulating activity.